Notch signaling regulates mammary stem cell function and luminal cell-fate commitment.
The recent identification of mouse mammary stem cells (MaSCs) and progenitor subpopulations has enhanced the prospect of investigating the genetic control of their lineage specification and differentiation. Here we have explored the role of the Notch pathway within the mammary epithelial hierarchy. We show that knockdown of the canonical Notch effector Cbf-1 in the MaSC-enriched population results in increased stem cell activity in vivo as well as the formation of aberrant end buds, implying a role for endogenous Notch signaling in restricting MaSC expansion. Conversely, Notch was found to be preferentially activated in the ductal luminal epithelium in vivo and promoted commitment of MaSCs exclusively along the luminal lineage. Notably, constitutive Notch signaling specifically targeted luminal progenitor cells for expansion, leading to hyperplasia and tumorigenesis. These findings reveal key roles for Notch signaling in MaSCs and luminal cell commitment and further suggest that inappropriate Notch activation promotes the self-renewal and transformation of luminal progenitor cells.
Bouras
Toula
T
VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Pal
Bhupinder
B
Vaillant
François
F
Harburg
Gwyndolen
G
Asselin-Labat
Marie-Liesse
ML
Oakes
Samantha R
SR
Lindeman
Geoffrey J
GJ
Visvader
Jane E
JE
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019521:Body Patterning / Q000235:genetics; D019070:Cell Lineage; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D005260:Female; D020869:Gene Expression Profiling; D006965:Hyperplasia; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D014161:Transduction, Genetic
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497762:Notch1 protein, mouse; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1